rs28729117

Variant names:

• chr2-201757786-T-C
• rs28729117
• NM_020919.4:c.1114-27A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020919.4(ALS2):​c.1114-27A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,504,302 control chromosomes in the GnomAD database, including 23,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2498 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20770 hom.)
• Consequence: ALS2 NM_020919.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.02
• Publications: 2 publications found

Genes affected

ALS2 (HGNC:443): (alsin Rho guanine nucleotide exchange factor ALS2) The protein encoded by this gene contains an ATS1/RCC1-like domain, a RhoGEF domain, and a vacuolar protein sorting 9 (VPS9) domain, all of which are guanine-nucleotide exchange factors that activate members of the Ras superfamily of GTPases. The protein functions as a guanine nucleotide exchange factor for the small GTPase RAB5. The protein localizes with RAB5 on early endosomal compartments, and functions as a modulator for endosomal dynamics. Mutations in this gene result in several forms of juvenile lateral sclerosis and infantile-onset ascending spastic paralysis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ALS2 Gene-Disease associations (from GenCC):

• ALS2-related motor neuron disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• amyotrophic lateral sclerosis type 2, juvenile

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• infantile-onset ascending hereditary spastic paralysis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• juvenile primary lateral sclerosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-201757786-T-C is Benign according to our data. Variant chr2-201757786-T-C is described in ClinVar as [Benign]. Clinvar id is 261365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4	c.1114-27A>G		intron_variant	Intron 4 of 33	ENST00000264276.11	NP_065970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11	c.1114-27A>G		intron_variant	Intron 4 of 33	1	NM_020919.4	ENSP00000264276.6

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25719 AN: 151986 Hom.: 2498 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.161

GnomAD2 exomes AF: 0.218 AC: 43400 AN: 199222 AF XY: 0.223

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.450

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.160 AC: 216950 AN: 1352198 Hom.: 20770 Cov.: 22 AF XY: 0.165 AC XY: 111931 AN XY: 676454

African (AFR) AF: 0.203 AC: 6180 AN: 30400

American (AMR) AF: 0.142 AC: 5973 AN: 41960

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4454 AN: 25312

East Asian (EAS) AF: 0.418 AC: 15918 AN: 38062

South Asian (SAS) AF: 0.324 AC: 26769 AN: 82660

European-Finnish (FIN) AF: 0.211 AC: 8314 AN: 39372

Middle Eastern (MID) AF: 0.172 AC: 929 AN: 5400

European-Non Finnish (NFE) AF: 0.134 AC: 138233 AN: 1032316

Other (OTH) AF: 0.179 AC: 10180 AN: 56716

GnomAD4 genome AF: 0.169 AC: 25737 AN: 152104 Hom.: 2498 Cov.: 32 AF XY: 0.175 AC XY: 13027 AN XY: 74346

African (AFR) AF: 0.186 AC: 7713 AN: 41482

American (AMR) AF: 0.121 AC: 1853 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 597 AN: 3468

East Asian (EAS) AF: 0.405 AC: 2096 AN: 5180

South Asian (SAS) AF: 0.337 AC: 1623 AN: 4822

European-Finnish (FIN) AF: 0.223 AC: 2358 AN: 10576

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9048 AN: 67996

Other (OTH) AF: 0.161 AC: 339 AN: 2108

Alfa AF: 0.161 Hom.: 556

Bravo AF: 0.163

Asia WGS AF: 0.370 AC: 1284 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.086
DANN	Benign	0.42
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28729117; hg19: chr2-202622509; COSMIC: COSV51885346; COSMIC: COSV51885346;